This invention relates to new lipodepsipeptide antibiotics and methods for preparation of these compounds; and more particularly, a method for preparing novel depsipeptide intermediates from the A21978 antibiotic complex for the purpose of preparing new types of biologically potent lipsipeptides.
Daptomycin, which is derived from the A21978 complex, is a lipodepsipeptide antibiotic that is currently undergoing clinical trials (Drugs Future, 2001, 26(7)); F. P. Tally et al., Exp Opin. Invest. Drugs (1999)8(8): 1223-1238) and has shown excellent activity against gram positive bacteria including strains of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Due to resistance of the bacteria, human infections with the MRSA and VRE organisms are very difficult to treat with antibiotics now commercially available. Although daptomycin represents a new structure type for clinically used antibiotics and is active against these infections, its use appears limited by toxicity and a new generation antibiotic in this family with reduced toxicity is needed. A number of derivatives of daptomycin have recently been reported in an effort to accomplish this goal (J. Hill et al., International PCT publication numbers WO 01/44271 A2, WO 01/44272 and WO 01/44274). These and previously reported derivatives are based on building new molecules by adding onto the existing core depsipeptide unit of daptomycin in order to obtain biologically active compounds.
Accordingly, the primary object of the present invention is to provide potent and effective antibiotics for treating gram positive bacteria, without limiting use because of toxicity.
A further object of the present invention is to provide lipodepsipeptide antibiotics, derived from the A21978 complex by selective removal of one to three amino acids of the exocyclic tripeptide side chain of the depsipeptide unit, and then derivatizing the result.
A further and more particular object is to provide non-toxic antibiotics particularly active against gram positive bacterial infections by preparing derivatives of the exocyclic peptide side chain of the depsipeptide unit, after removing one to three amino acids from the side chain.
These and other objects of the present invention are accomplished in an antibiotic which is prepared from three depsipeptide intermediates of the A21978 antibiotic complex. The A21978 complex is obtained by fermentation of Streptomyces roseosporus, according to procedures described in U.S. Pat. No. 4,331,594. The ornithine amino group of the A21978 antibiotic complex is then protected by a group, such as 9-fluorenylmethoxycarbonyl (FMOC), or a group from a solid phase support. The product from this reaction is treated with a deacylase enzyme to provide a single protected peptide by removal of the acyl side chain from the components of the complex by procedures described by Debono, et al, in the Journal of Antibiotics, Volume XLI, No. 8, pages 1093-1105. By a sequence of modified Edman degradations or enzymatic reactions, the protected forms of new intermediates are obtained in the form of cyclodepsipeptides. Semi-synthetic antimicrobial lipodepsipeptides are prepared from the cdpeptides. Thus, three different core cdpeptides are elaborated to produce anti-microbial derivatives. The exocyclic tripeptide side chain of the depsipeptide unit is reduced in size by one to three amino acids and then derivatized to produce potent antibiotics.